Pharmaceutically active aza-bicyclo-benzamide derivatives

ABSTRACT

This invention relates to novel substituted benzamides having useful pharmacological properties, to pharmaceutical compositions containing them, and to a process for their preparation. 
     N-(2-Diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide, 1-ethyl-2(2-methoxy-5-sulphamoylbenzamidomethyl)pyrrolidine and N-[4&#39;-(1&#34;-benzyl)-piperidyl]-2-methoxy-4-amino-5-chlorobenzamide are well known compounds having useful pharmacological activity such as the ability to regulate the gastro-intestinal function anti-emetic activity and CNS activity. 
     It has now been found that a certain structurally distinct class of substituted benzamides also has useful pharmacological activity, in particular dopamine antagonist activity.

Accordingly, the present invention provides a compound of the formula (I), and pharmaceutically acceptable salts thereof: ##STR1## wherein: R₁ is a C₁₋₆ alkoxy group;

R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇ acyl, C₂₋₇ acylamino, or amino, aminocarbonyl or aminosulphone optionally substituted by one or two C₁₋₆ alkyl groups, C₁₋₆ alkylsulphone or nitro;

R₅ is hydrogen or C₁₋₆ alkyl;

R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 0 to 2 and R₇ is a C₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₈ where t is 1 or 2 and R₈ is C₂₋₅ alkenyl or a phenyl group optionally substituted by one or two substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen; and

n, p and q are independently 0 to 2.

Suitable examples of the group R₁ include methoxy, ethoxy and n- and iso-propoxy. Preferably R₁ is a methoxy group.

Suitable examples of the groups R₂ and R₃ include the following groups: hydrogen, chlorine, bromine, CF₃, acetyl, propionyl, n- and iso-butyryl, acetylamino, propionylamino, n- and iso-butyrylamino, amino, aminocarbonyl, aminosulphone, amino, aminocarbonyl and aminosulphone substituted by one or two methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl groups; and methyl, ethyl or n- and iso-propylsulphones, and nitro.

Particularly suitable R₂ and R₃ groups include hydrogen, halogen, acyl, amino, and acylated amino as defined.

It is generally preferred that R₂ is in the 4-position relative to the carbonyl side chain for greater activity in the resultant compound of the formula (I). For the same reason it is generally preferred that R₃ is in the 5-position relative to the carbonyl side chain.

Particularly preferred R₂ groups include 4-amino and 4-(acylated amino) as defined. Preferably R₂ is 4-amino. Particularly preferred R₃ groups include 5-halo, such as 5-chloro.

Often the amide and side chain nitrogen atoms are separated by a minimum of 2 or 3 carbon atoms, preferably 3.

Suitable examples of R₅ include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, preferably hydrogen or methyl, in particular hydrogen.

Suitable examples of R₆ when C₁₋₇ alkyl include methyl, ethyl, n- and iso-propyl and n-, sec-, iso- and tert-butyl, n-pentyl, n-hexyl and n-heptyl.

Within C₁₋₇ radicals, C₁₋₄ alkyl are particularly useful (as hereinafter described).

Suitable examples of R₆ when C₁₋₄ alkyl include methyl, ethyl, n- and iso-propyl and n-, sec-, iso- and tert-butyl, particularly methyl, n-propyl and iso-butyl.

Similarly, within C₁₋₇ radicals, C₅₋₇ alkyl are also of interest (as hereinafter described).

Suitable examples of R₆ when C₅₋₇ alkyl include n-pentyl, n-hexyl and n-heptyl.

When R₆ is a group --(CH₂)_(s) R₇ as defined, suitable examples of R₇ include C₅₋₈ cycloalkyl, preferably cyclohexyl. s is preferably 1.

When R₆ is a group --(CH₂)_(t) R₈ as defined, t is preferably 1.

In such a group R₆, when R₈ is C₂₋₅ alkenyl, suitable examples thereof include vinyl, prop-1-enyl, prop-2-enyl, 1-methylvinyl,but-1-enyl, but-2-enyl, but-3-enyl, 1-methylenepropyl, 1-methylprop-1-enyl and 1-methylprop-2-enyl, in their E and Z forms where stererisomerism exists.

A preferred C₁₋₅ alkenyl R₈ radical is vinyl, so that R₆ is preferably allyl.

When R₈ is optionally substituted phenyl as defined above, suitable examples of such optional phenyl substitutents include methyl, ethyl, n- and iso-propyl, n, sec- and tert-butyl; methoxy, ethoxy, n- and iso-propoxy; CF₃, fluoro, chloro or bromo. Preferably R₈ when optionally substituted phenyl is unsubstituted.

Compounds of the formula (I) wherein R₆ is --(CH₂)_(s) R₇ and --(CH₂)_(t) R₈ as defined, and wherein R₆ contains at least 5 carbon atoms, are of particular interest because of their beneficial pharmacological activity (as hereinafter discussed). In such compounds R₆ is preferably benzyl.

n is preferably 0. q is suitably 0 to 1, preferably 1. p is suitably 0 to 1, preferably 0.

It is greatly preferred for higher activity that the bond between the benzamide moiety and the cyclic side chain (ie between the R₅ substituted nitrogen atom and the (CH₂)_(n) moiety) in the compounds of formula (I) is equatorial.

The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with conventional acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid and the like.

The pharmaceutically acceptable salts of the compounds of the formula (I) also include quaternary ammonium salts. Examples of such salts include such compounds quaternised by compounds such as R₉ -Y wherein R₉ is C₁₋₆ alkyl, phenyl - C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and Y is an anion of an acid. Suitable examples of R₉ include methyl, ethyl and n- and iso-propyl; and benzyl and phenylethyl. Suitable examples of Y include the halides such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internal salts such as N-oxides.

The compounds of the formula (I) can also form hydrates.

A group of compounds within those of the formula (I) consists of those wherein:

R₁ is a C₁₋₆ alkoxy group;

R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇ acyl, amino, C₂₋₇ acyl amino, aminocarbonyl or aminosulphone optionally substituted by one or two C₁₋₆ alkyl groups; C₁₋₆ alkylsulphone or nitro groups;

R₅ is hydrogen or C₁₋₆ alkyl;

R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 1 or 2 and R₇ is a C₃₋₈ cycloalkyl group, or a phenyl group optionally substituted by one or two substitutents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen; and

n, p and q are independently 0 to 2.

From the aforesaid it will be seen that in a preferred aspect the moiety of formula (II): ##STR2## in a compound of the formula (I) will have the structure (III): ##STR3## In a preferred group of compounds within those of formula (I) and pharmaceutically acceptable salts thereof, the moiety of formula (II) will be of the formula (III), and the moiety of formula (IV): ##STR4## will have the formula (V): ##STR5## wherein the variables are as defined in formula (I), so that these preferred compounds of the formula (I) are of the formula (VI): ##STR6## wherein the variables are as defined in formula (I).

More suitably p is 0 or 1, it is believed preferably 0. Preferably q is 1 and the moiety of formula (III) is then attached at a position para to the N-atom.

Suitable and preferred examples of R₆ in formula (VI) include those listed under formula (I) for R₆. Particularly preferred examples of R₆ include C₁₋₇ alkyl and cyclohexylmethyl. Particularly preferred examples of R₆ also include benzyl optionally substituted in the phenyl ring as defined under formula (I). Unsubstituted benzyl is especially preferred.

A particularly preferred sub-group of compounds within those of formula (VI) are those of the formula (VII): ##STR7## wherein R¹ ₆ is C₁₋₄ alkyl.

Suitable examples of R¹ ₆ are as so described for R₆ C₁₋₄ alkyl under formula (I).

It is preferred that the moiety of the formula (III) is in the β-orientation to the nortropane ring.

Another particularly preferred sub-group of compounds within those of formula (VI) are those of the formula (VIII): ##STR8## wherein R² ₆ is C₅₋₇ alkyl; a group --(CH₂)_(t) R¹ ₈ wherein t is 1 or 2 and R¹ ₈ is optionally substituted phenyl as defined in formula (I); or cyclohexylmethyl.

Suitable and preferred R² ₆ are as so described for the corresponding R₆ groups under formula (I).

R² ₆ benzyl is especially preferred.

It is preferred that the moiety of the formula (III) is in the β-orientation to the nortropane ring.

A sub-group of compounds within those of the formula (VI) of interest are those of the formula (IX): ##STR9## wherein R₆ ¹ is as defined in formula (VII).

Suitable examples of R₆ ¹ are as so described under formula (VII).

Another sub-group of compounds within those of the formula (VI) of interest are those of the formula (X): ##STR10## wherein R² ₆ is as defined in formula (VIII).

Suitable and preferred examples of R² ₆ are as so described under formula (VIII).

In a second group of compounds of interest the moiety of formula (II) will have the structure (III) as hereinbefore depicted and defined, but the moiety of formula (IV) will have the structure (XI): ##STR11## wherein n' is 1 or 2 and the remaining variables are as defined in formula (I).

More suitably p and q independently are 0 or 1; preferably p is 0 and q is 1.

Suitable and preferred examples of R₆ include those listed hereinbefore for R₆. Particularly preferred examples of R₆ include benzyl optionally substituted in the phenyl ring as defined under formula (I). Unsubstituted benzyl is especially preferred.

Particularly suitable examples of the compounds of the present invention include those specifically prepared in the Examples which form a later section in this specification. These are:

4-acetamido-5-chloro-2-methoxy-N-(3α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-methyl-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-methyl-(3'-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

5-sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide,

2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzyl methobromide

4-amino-5-chloro-2-methoxy-N-(3α'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3β'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-methylbenzyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-methoxybenzyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-ethoxybenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-chlorobenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[3",4"-dichlorobenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]-octyl)-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-methyl-8'-azabicyclo[3.2.1]-octyl)-benzamide

4-acetamido-5-chloro-2-methoxy-N-(3'α-[8'-methyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[9'-methyl-9'-azabicyclo[3.3.1]nonyl benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[9'-methyl-9'-azabicyclo[3.3.1]-nonyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-ethyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-ethyl-8'-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-iso-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'α-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-secbutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-isobutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexylmethyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl])benzamide,

4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl]benzamide,

4-amino-5-chloro-2-methoxy-N-(3'β-[8'-allyl-8-azabicyclo[3.2.1]octyl])benzamide,

5-chloro-2-methoxy-4-methylamino-N-(3β-[8'-benzyl-8-azabicyclo[3.2.1]octyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-methyl-"-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-emthoxy-N-(2'-(-)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(+)-α-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(-)-α-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide,

4-amino-5-chloro-2-methoxy-N-(4'-(+)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide, and

4-amino-5-chloro-2-methoxy-N-(4'-(-)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide

It will of course be realised that the compounds of the formula (I) have chiral or prochiral centres, and thus are capable of existing in a number of stereoisomeric forms. The invention extends to each of these stereoisomeric forms, and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.

The invention also provides a process for the preparation of a compound of the formula (I), which process comprises reacting an acid of the formula (XII): ##STR12## or a reactive derivative thereof, with a compound of formula (XIII): ##STR13## wherein R₁₀ is hydrogen or R₆ as defined in formula (I), the remaining variable groups being as defined in formula (I); and thereafter if desired or necessary converting a group R₂ or R₃ in the thus formed compound to another group R₂ or R₃ respectively; converting R₁₀ when hydrogen to R₆ ; and optionally forming a pharmaceutically acceptable salt of the resultant compound of the formula (I).

`Reactive derivative` when used herein means a derivative of the compound (XII) which can be reacted with the compound (XIII) to form an amido linkage between the acid group of the compound (XII) and the amino group of the compound of the formula (XIII).

Often this reactive derivative will be the acid halide, such as the acid chloride, of the acid (XII). In such cases, the reaction will normally be carried out in an inert solvent, preferably in the presence of an acid acceptor. The inert solvent can be any solvent inert to both reactants, such as benzene, toluene, diethyl ether or the like. The acid acceptor is suitably an organic base such as a tertiary amine e.g. triethylamine, trimethylamine, pyridine or picoline, or an inorganic acid acceptor, such as calcium carbonate, sodium carbonate, potassium carbonate or the like. It should also be noted that it is possible to use certain acid acceptors as the inert solvent, for example organic bases.

Another useful reactive derivative of the acid (XII) that may be used is an ester, such as a methyl, ethyl, propyl or butyl ester, in which case the reaction is normally carried out by heating the reactants together in an inert solvent such as ethylene glycol.

The reaction may also be carried out by forming an anhydride of the acid (XII) in the usual manner, and reacting that with the compound (XIII); normally a conventional mixed anhydride will be used; or by reacting the acid (XII) and the compound (XIII) in the presence of a dehydrating catalyst such as a carbodiimide, for example dicyclohexylcarbodiimide.

The intermediates of the formulae (XII) and (XIII) are either known compounds or can be prepared by analogous processes to known compounds.

It will be realised that in the compound of the formula (I) the --CO--NR₅ --(CH₂)_(n) -- linkage may have an α or β orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of α and β isomers of the compound of the formula (I) may be synthesised nonstereospecifically and the desired isomer separated conventionally therefrom, e.g. by chromatography; or alternatively the α or β isomer may if desired be synthesised from the corresponding α or β form of the compound of the formula (XIII).

Synthesis from the corresponding α or β isomer of the compound of the formula (XIII) is in general preferred.

The α or β form of the compound of the formula (XIII) may if desired be prepared by known stereospecific processes, such as those leading to the α or β isomers of the compound of the formula (XIII) depicted in the Scheme and described in Descriptions 3C, 4A and 4C and Descriptions 2 and 3A and B respectively.

The precursor of the compound of the formula (XIII) may be stereospecifically synthesised, such as the azide (D3) of Description 2, and then converted to the corresponding desired isomer of the compound of the formula (XIII) under non-stereospecific conditions with retention of configuration. Alternatively, the precursor may itself have no asymmetric centre at the relevant position, such as the oximes and imines of Descriptions 3 and 4, but be converted under stereospecific conditions to the desired isomer of the compound of the formula (XIII).

Alternatively, a mixture of the α and β isomers of the compound of the formula (XIII) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography. However, in this case it is generally more convenient to react the mixture to give a mixture of α and β isomers of the compound of the formula (I) and to separate these if desired as hereinbefore described.

The following Scheme 1 illustrates stereospecific and non-stereospecific synthetic routes to intermediates of the formula (XIII) wherein n is 0. ##STR14## The following Scheme 2 illustrates preparative routes to intermediates of the formula (XIII) wherein n is 1 or 2. ##STR15##

The acid addition salts of compounds of the formula (I) may be prepared in entirely conventional manner by reacting a compound of the formula (I) in base form with the chosen acid.

The quaternary ammonium salts of the compounds of the formula (I) may be prepared in conventional manner for such salts, such as by reaction of the chosen compound of the formula (I) with a compound R₉ Y as defined. This reaction is suitably carried out in an appropriate solvent such as acetone, methanol, ethanol, dimethylformamide and the like, at ambient or raised temperature and pressure.

The nitrogen atom of the moiety of formula (IV) may also form an N-oxide to give an internal N-oxide salt of the compound of the formula (I). The N-oxides may be prepared in conventional manner such as by reaction of the chosen compound of the formula (I) with an organic per-acid, such as m-chloroperbenzoic acid. This reaction is suitably carried out at below-ambient temperature in an organic solvent, preferably a chlorinated hydrocarbon solvent.

The interconversion of suitable groups R₂ and R₃ after formation of a compound of the formula (I) or corresponding intermediate therefor may be carried out by conventional methods. By way of example nitro groups may be reduced to amino groups in the normal manner, and acylamino groups may be converted to amino groups also by conventional methods. Also a compound of the formula (I) wherein R₂ or R₃ is halogen can be prepared by a conventional halogenation of the corresponding compound of the formula (I) wherein the said R₂ or R₃ is hydrogen. Accordingly it will be realised that compounds of the formula (I) containing an R₂ or R₃ group which is convertible to another R₂ or R₃ group are useful intermediates, and as such form an important aspect of the invention.

Conversion of R₁₀ when hydrogen to a group R₆ as hereinbefore defined may be carried out conventionally, for example by reacting the product of the reaction of the compounds of the formulae (XII) and (XIII) with a compound QR₆ wherein R₆ is as defined in formula (I) and Q is a group or atom readily displaced by a nucleophile.

Suitable values for Q include Cl, Br, I, OSO₂ CH₃ or OSO₂ C₆ H₄ pCH₃.

Favoured values for Q include Cl, Br and I.

Particularly suitably the compound QR₄ is a benzyl halide such as benzyl bromide or benzyl chloride.

The reaction may be carried out under conventional alkylation conditions for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at a non-extreme temperature such as at ambient or at a slightly elevated temperature.

It will be appreciated that, when R₂ or R₃ are converted to other R₂ or R₃ and R₅ being hydrogen is converted to R₄, then these conversions may take place in any desired or necessary order.

As hereinbefore stated, the compounds of the formula (I) are dopamine antagonists.

Depending on their balance between peripheral and central action, the compounds of the formula (I) may be used in the treatment of disorders related to impaired gastro-intestinal motility, such as retarded gastric emptying, dyspepsia, flatulence, oesophagal reflux, peptic ulcer and emesis, and/or in the treatment of disorders of the central nervous system, such as psychosis,

All the compounds of the formula (I) may be used in the treatment of emesis.

Examples of compounds of the formula (I) which are of particular interest for their motility enhancing activity are those wherein P₆ contains 1 to 4 carbon atoms, such as C₁₋₄ alkyl, especially those of formulae (VII) and (IX).

Examples of compounds of the formula (I) which are of particular interest for their CNS activity, and for their anti-emetic activity, are those wherein R₆ contains 5 or more carbon atoms, particularly benzyl, such as those of formulae (VIII) and (X).

The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I), or a hydrate or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. Such compositions may be adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions and the like; the compositions may also be in the form of suppositories and the like. Normally, orally administrable compositions are preferred.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented in a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehciles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

It will of course be realised that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.

The invention further provides a method of treatment of maladies in humans comprising the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. The "effective amount" will depend in the usual way on a number of factors such as the nature and severity of the malady to be treated, the weight of the sufferer, and the actual compound used.

However by way of illustration, unit doses will suitably contain 0.1 to 20 mgs of the compound of formula (I), for example 0.5 to 10 mgs.

Again by way of illustration, such unit doses will suitably be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, in such a way that the total daily dose is suitably in the range 0.01 to 10 mg/kg per day.

Compounds of the formula (I) have the ability to potentiate the effect of conventional analgesics in migraine treatment when administered concurrently with the analgesic.

Thus the invention provides a pharmaceutical composition comprising a compound of the formula (I) and an analgesic.

The compound of the formula (I) and the analgesic, such as aspirin or paracetamol, will be present in the composition in amounts generally similar to their usual effective dose.

The composition can be a combination product, for example a tablet or capsule containing both a compound of the formula (I) and an analgesic for oral administration, or a twin pack comprising the two active ingredients made up for separate administration.

The invention accordingly provides a method of treatment of migraine comprising the administration to the sufferer of a compound of the formula (I) and an analgesic.

The following Examples illustrate the preparation of the compounds of formula (I) and the following Descriptions illustrate the preparation of intermediates thereto.

Nomenclature note: Tropane is 8-methyl-8-azabicyclo [3.2.1]octane and derivatives thereof are named accordingly in the following Descriptions

DESCRIPTION 1 3α,β-amino-8-benzyl-8-azabicyclo-[3,2,1]octane (D1); intermediate for Compounds 1 to 3; mixture of 3α-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D26) and 3β-amino-8-benzyl-8-azabicyclo [3.2.1]octanec (D4) ##STR16##

8-benzylnortropan-3-one oxime (6 g) was Soxhlet extracted for 15 hours into a stirred suspension of lithium aluminum hydride (2.4 g) in dry THF (150 ml). The mixture was hydrolysed.

Fractional distillation under reduced pressure afforded 3-amino-8-benzylnortropane (D1) (4.2 g, 75%) as a mixture of 3α and 3β isomers. b.pt. 107°-10° C./0.2 mm Hg.

DESCRIPTION 2A 3β-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D4); intermediate for Compounds 4 and 5 ##STR17## (a) 8-benzyl-3-nortropanol (D2)

8-benzyl-3-nortropanone (3.9 g) was reduced with lithium aluminium hydride (1.0 g) in diethyl ether to 8-benzyl-3-nortropanol (D2) by the method of R. Mirza et al., Nature, 1952, 170, 630. This is claimed by Mirza to give stereospecifically the β-isomer but later workers¹ have shown that a mixture of α and β isomers is produced.

(b) 3β-azido-8-benzylnortropane (D3)

Crude 8-benzyl-3-nortropanol (D2) (3.9 g.) was reacted with successively, triphenylphosphine (4.7 g) and diethyl azodicarboxylate (3.2 g), and diphenylphosphorylazide (5 g) in THF by the method of A. K. Bose et al., Tetrahedron Letters, 1977, 23, 1977, to yield 3β-azido-8-benzyl-nortropane (D3) as an oil (2 g, 25%). i.r. 2100 cm⁻¹ (γN₃).

(c) 3β-amino-8-benzylnortropane (D4)

To a stirred suspension of lithium aluminum hydride (0.5 g) in diethyl ether (50 ml) was added a solution of 3β-azido-8-benzylnortropane (D3) (2 g) in diethyl ether (10 ml.), and the reaction was stirred at ambient temperature for 3 hours. Hydrolysis, extraction with ethyl acetate and removal of the solvent afforded crude 3β-amino-8-benzylnortropane (1.1 g, 60%) used in the procedure of Example 2 without further purification. N.B. The assignment of β-configuration to the azide (D3) and amine (D4) is based on the fact that Compound 5 attained via amine (D4) was identical with the β-isomer obtained via the stereospecific route outlined in Description 3β and Example 5.

DESCRIPTION 2B 3β-amino-8-(4'-chlorobenzyl)-8-azabicyclo[3.2.1]octane (D5); intermediate for Compound 16

N-(4-chlorobenzyl)-nortropanone (2.02 g., 8.1 mmole) in methanol (100 ml) was treated with sodium borohydride (0.75 g.). This was stirred at ambient temperature for 12 hours, then poured into saline solution. It was made strongly basic with dilute aqueous sodium hydroxide, and the resulting mixture was extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried (sodium sulphate), filtered and evaporated to yield a mixture of α- and β-N-(4-chlorobenzyl)-nortropanols (2.02 g., 99%).

The mixture of isomeric tropanols from above was converted to 3β-azido-8-(4-chlorobenzyl)-nortropane by the method described in Description 2A. Thus N-(4-chlorobenzyl)-nortropanol (3.3 g., 13.1 mmoles) was successively treated with triphenylphosphine (3.77 g.), diethylazodicarboxylate (2.49 g) and diphenylphosphoryl azide (4.1 g.) in THF to yield, after work up and chromatography to separate the isomeric azide 3β-azido-8-(4-chlorobenzyl)-nortropane (1.1 g., 30.5%) as an oil.

This was reduced with lithium aluminium hydride in ether under reflux for 12 hours. Hydrolysis, extraction with ethyl acetate and removal of solvent afforded crude 3β-amino-8-(4-chlorobenzyl)-nortropane (0.82 g., 82%).

3β-amino-8-(3',4'-dichlorobenzyl)-8-azabicyclo[3.2.1]octane (D6); intermediate for Compound 17 was prepared analogously (32%)

DESCRIPTION 3A 3β-amino-8-methyl-8-azabicyclo[3.2.1]octane (D8), intermediate for Compound 19 ##STR18## (a) Tropinone oxine (D7)

Tropinone (3.68 g; 0.0265 mole) was dissolved in ethanol (50 ml) containing pyridine (4-5 ml) and treated with hydroxylamine hydrochloride (1.90 g). The mixture was heated under reflux for 30 minutes, cooled, treated with solid potassium carbonate (ca. 10 g) and water (ca. 5 ml). The ethanol was removed in vacuo and the mixture extracted with chloroform (3×150 ml). The combined extracts were dried K₂ CO₃), filtered and evaporated in vacuo. The resulting solid was recrystallised from ethyl acetate/petrol ether 40-60 to yield tropinoneoxime (3.1 g; 76%) as colourless crystals m.pt 114°-115° C.

(b) 3β-amino-8-methyl-8-azabicyclo[3.2.1]-octane (D8)

Tropinone oxime (3.08 g; 0.02 mole) was dissolved in anhydrous amyl alcohol (100 ml) and heated to almost boiling. Sodium (ca. 3.0 g) was added portionwise over 1 hour then the mixture left to cool overnight. The mixture was treated with 5 N hydrochloric acid (ca. 80 ml), and extracted with ethyl acetate (3×150 ml). The acidic aqueous layer was separated, basified with sodium hydroxide and re-extracted with ethyl acetate (4×150 ml) and the combined extracts were dried (K₂ CO₃) filtered and evaporated in vacuo to yield (D8) (2.25 g; 80%) as a colourless oil, used without further purification.

DESCRIPTION 3B 3-β-amino-8-benzyl-8-azabicyclo[3.2.1]octane (D4); intermediate for Compound 5 ##STR19##

Similarly, sodium (2 g) was added portionwise over 2 hours to a stirred solution of 8-benzylnortropan-3-one oxime (0.9 g) in amyl alcohol (20 ml) at reflux. The solution was cooled diluted, with diethyl ether and acidified with excess dilute hydrochloric acid. The acid extract was washed with diethyl ether and then basified with excess potassium carbonate. Extraction with ethyl acetate followed by evaporation of solvent afforded crude 3β-amino-8-benzylnortropane (d4) (0.85 g) used in the procedure of Example 5 without purification.

The following intermediates were analogously prepared from the corresponding oximes:

3α,β-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D9) mixture of 3α-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D10); and 3β-amino-9-benzyl-9-azabicyclo[3.3.1]-nonane (D11); intermediates for Compounds 11 and 12 respectively ##STR20## and as oils. The following intermediates of the general formula ##STR21## were prepared analogously

    ______________________________________                                         Intermediate                   For     Yield                                   No.        R.sub.6       n     Compound                                                                               %                                       ______________________________________                                         D12                                                                                        ##STR22##    0     13      97.6                                    D13                                                                                        ##STR23##    0     14      71                                      D14                                                                                        ##STR24##    0     15      94                                      D15        CH.sub.2 CH.sub.2 Ph                                                                         0     18      83                                      D16        Me            1     22      60                                      D17        Et            0     23      93                                      D18        Pr.sup.n      0     24      97                                      D19        Pr.sup.i      0     25      71                                      D20        Bu.sup.n      0     26      60                                      D21        CH.sub.2 . Pr.sup.i                                                                          0     28      74                                      D22        CH(Me)Et      0     29      50                                      D23                                                                                        ##STR25##    0     30      78                                      D24                                                                                        ##STR26##    0     31      66                                      D30        CH.sub.2 CHCH.sub.2                                                                          0     32                                              ______________________________________                                    

DESCRIPTION 3C 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane (D15); intermediate for Compound 21 ##STR27##

N-methyl-9-azabicyclo-[3.3.1]-nonan-3-one oxime (3.25 g., 0.02 mole) was dissolved in ethanol and hydrogenated over Raney nickel in the presence of ammonium acetate at 300 p.s.i. at 50° C. for 24 hours. The mixture was filtered, evaporated in vacuo, dissolved in dilute hydrochloric acid, basified and extracted into ethyl acetate. The combined organic layers were dried (K₂ CO₃), filtered and evaporated in vacuo to yield 3-amino-9-methyl-9-azabicyclo-3.3.1]-nonane (2.67 g., 90%), used without further purification.

The product is a single diastereomer believed to be the α-isomer.

DESCRIPTION 3D 3α-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D10 ); intermediate for Compound 11

9-Benzyl-9-azabicyclo-(3.3.1)-nonan-3-one oxime (4.0 g; 0.0164 mole), m.p. 134°, was dissolved in ethanol (100 ml) and hydrogenated at 50°-60° at 250 psi in the presence of Raney nickel. The mixture was filtered after 24 hours through kieselguhr and evaporated in vacuo. The resulting oil was dissolved in dilute hydrochloric acid (50 ml) extracted with ethyl acetate (3×150 ml), the aqueous layer was basified and re-extracted with ethyl acetate (3×150 ml). The combined organic extracts were dried (K₂ CO₃), filtered and evaporated in vacuo to yield 3-amino-9-benzyl-9-azabicyclo-[3,3,1]-nonane (2.3 g; 61%), used without further purification.

DESCRIPTION 4A 3α-amino-8-benzyl-8-azabicyclo[3.2.1]octane, (D6); intermediate for compound 6 ##STR28##

8-benzyl-8-azabicyclo-[3.2.1]-octan-3-one (4.40 g, 0.02 mole) was treated with excess methylamine in ethanol (50 ml), heated to 60°-70°, then hydrogenated in the presence of pre-reduced platinum (400 mg) to give 8-benzyl-3α-methylamino-8-azabicyclo-[3.2.1]-octane (3.33 g, 72%), m.p. 77°-79°.

DESCRIPTION 4B 3α,β-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane (D27); mixture of 3α-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane (D26) and 3β-methylamino-8-benzyl-8-azabicyclo[3.2.1]-octane (D28); intermediates for Compounds 6 and 7 respectively ##STR29##

N-benzyl-nortropinone (4.30 g, 0.02 mole) was treated with excess methylamine in anhydrous toluene. Titanium tetrachloride (50 ml. of 10% solution in xylene) was added and the mixture stirred for 2 days. The resulting mixture was filtered through kieselguhr and evaporated in vacuo to give N-benzyl-3-methylimino-nortropane (5.0 g).

A solution of N-benzyl-3-methylamino-nortropane (5.0 g) in methanol (100 ml) was treated portionwise with sodium borohydride (ca 5.0 g) and the mixture left to stir at room temperature for 3 hours. Water (50 ml was added and the mixture extracted with ether (3×100 ml). The combined organic extracts were dried (K₂ CO₃), filtered and evaporated in vacuo to give 3-methylamino-8-benzyl-8-azabicyclo[3.2.1]octane (D27) as a mixture of the axial (D26) and equatorial (β) (D28) isomers (ca. 60:40) as shown by proton magnetic resonance spectrum.

DESCRIPTION 4C 3α-amino-8-butyl-8-azabicyclo[3.2.1]octane (D29); intermediate for Compound 27 ##STR30##

N-n-butylnortropinone (5.0 g, 0.028 mole) in ethanol (50 ml) was treated with ethanolic ammonia and left to stand for 24 hours. The mixture was hydrogenated over Raney nickel for 24 hours at 300 p.s.i. in the presence of ammonium acetate (2.5 g.). The mixture was filtered, evaporated in vacuo, treated with H₂ O, and extracted with ethyl acetate. The combined organic extracts were acidified and separated. Basification of the aqueous layer and further extraction with ethyl acetate yielded (D29) (2.55 g., 50%), after drying (K₂ CO₃) and evaporation in vacuo which was used without further purification.

DESCRIPTION 5 2-aminomethyl-8-methyl-8-azabicyclo[3.2.1]octane (D31); intermediate for Compound 37 ##STR31##

Methyl isocyanide (5.04 g., 0.026 mol) was added to (±)-tropan-2-one (2 g., 0.0143 mol) in dimethoxyethane (80 ml) and the solution cooled to 0° C. Ethanol (2 ml) was added followed by addition of potassium tert-butoxide (5.64 g, 6.05 mol). The mixture was then heated at 50° C. for three hours, cooled and poured into a saturated potassium carbonate solution (300 ml). This was extracted with ethyl acetate (3×100 ml) and the combined extracts dried (K₂ CO₃), filtered and evaporated to give a crude oil which was abosorbed on alumina (40 g, grade 1 neutralised by addition of 10% water) from ethereal solution. The solution was eluted with a progressively graded mixture of ether, ethyl acetate and methanol to give 8-methyl-8-azabicyclo[3.2]octane-2nitrile (1.1 g-46%) as an oil.

The nitrile (1.1 g) in tetrahydrofuran (20 ml) was added to lithium aluminum hydride (0.5 g) in tetrahydrofuran (30 ml) and the mixture stirred for three hours. Water (0.5 ml), sodium hydroxide solution (10%) (0.75 ml) and water (1.25 ml) were added successively and the mixture filtered. The filtrate was dried (K₂ CO₃) and evaporated to give crude (D31) (1 g) as an oil.

The product is a racemate of a single diastereomer, believed to be the (±)-α-isomer.

DESCRIPTION 6 Pentachlorophenyl 5-chloro-2-methoxy-4-methylaminobenzoate (D32) ##STR32## 5-chloro-2-methoxy-4-methyl benzoic acid (2 g., 0.0093 mol) in dimethylformamide (50 ml) was treated with pentachlorophenyl trichloroacetate (4.5 g., 0.11 mol) and triethylamine (1.5 ml). The mixture was stirred at room temperature for one hour. The dimethylformamide was stripped off in vacuo, and the residue recrystallized from acetone/petroleum to give pentachlorophenyl 5-chloro-2-methoxy-4-methylaminobenzoate, m.pt 217°-219° C. EXAMPLE 1 4-acetamido-5-chloro-2-methoxy-N-(3α,β-[8'-benzyl]-8-azabicyclo[3.2.1]octyl)-benzamide (1) ##STR33##

To 4-acetamido-5-chloro-2-methoxybenzoyl chloride (6 g) in toluene (200 ml) and triethylamine (5 ml) was added 3αβ-amino-8-benzylnortropane (D1) (4.2 g) (prepared as in Description 1) in toluene (20 ml). The reaction mixture was stirred at room temperature for 2 hours. The mixture was treated with 2.5 N aqueous sodium hydroxide (20 ml), the toluene layer was separated and the aqueous layer was extracted with chloroform (3×150 ml) and the combined organic extracts were dried (K₂ CO₃). The solvent was removed therefrom and chromatography of the product (neutral alumina, Brockman II, ethyl acetate eluant) gave a mixture of 3'α and 3'β isomers of (1) as an oil (7.2 g, 84%).

EXAMPLE 2 4-amino-5-chloro-2-methoxy-N-(3'α, 8-[8'-benzyl]8-azabicyclo[3,2,1]octyl)benzamide (2) and 4-amino-5-chloro-2-methoxy-N-(3', α-[8'-benzyl]nortropyl) benzamide (3) ##STR34##

(1) (7.2 g) (prepared as in Example 1) was refluxed with an aqueous ethanol (water 10 ml ethanol (100 ml) solution of potassium hydroxide (2 g) for 3 hours. The mixture was then cooled to room temperature. The ethanol was removed by rotary evaporation. The residue was extracted with chloroform. The organic extracts were chromatographed (neutral alumina, Brockman II, ethyl acetate eluant) Bands containing (2) and (3) respectively were obtained, yielding (2) (3.3 g, 50%) and (3) (2.0 g, 30%).

(2) was shown by n.m.r. to be a 2:3 weight ratio mixture of the 3'α and 3'β isomers, and had a m.pt 159°-70° C.

    ______________________________________                                         Compound (3):                                                                  ______________________________________                                         m.p.t. 221-3° C.                                                        n.m.r.     8.10(s, 1H, aryl 6- --H)                                            (δ, CDCl.sub.3)                                                                     7.6-7.1 (m, 6H, Ph-- --H and CON --H)                                          6.30 (s, 1H, aryl 3- --H)                                                      4.6-4.2 (m, 3H, --N --H.sub.2, CONH . C --H═)                              3.93 (s, 3H, OC --H.sub.3)                                                     31/256 (s, 2H, PhC --H.sub.2 . N═)                                         3.4-3.1 (m, 2H, ═C --H--N(CH.sub.2 Ph)--CH═)                           2.3-1.5 (m, 8H, ═C --H.sub.2)                                   ______________________________________                                    

EXAMPLE 3 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide (4) ##STR35##

A solution of 4-acetamido-5-chloro-2-methoxybenzyl chloride (1.6 g) in toluene (100 ml) and triethylamine (2 ml) was treated with a solution of crude 3β-amino-8-benzylnortropane (D4) (1.1 g) (prepared as in Description 2) in toluene (20 ml), and the reaction was stirred at room temperature for 2 hours. The mixture was treated with 2.5 N aqueous sodium hydroxide solution (5 ml), the toluene layer was separated and the aqueous layer was extracted with ethyl acetate (3×50 ml). The solvent was removed from the combined, dried (K₂ CO₃) organic extracts to give an oil which crystallised on trituration with diethyl ether, furnishing 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]nortropyl)benzamide (4) (1.5 g, 70%). m.p.t. 185° C.

EXAMPLE 4 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide (5)

Compound (4) (prepared as in Example 3) (1.5 g) was hydrolysed in an aqueous ethanol (water 2 ml, ethanol 20 ml) solution of potassium hydroxide (0.5 g) under reflux for 2 hours, and the mixture was then diluted with water (50 ml), and then cooled to ambient temperature. The resulting precipitate was collected, dried and recrystallized (ethyl acetate/petrol) to give pure 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]8-azabicyclo[3.2.1]octyl)benzamide (5) (1.1 g, 80%)

m.p.t. 188° C.

    ______________________________________                                         n.m.r. (δ CDCl.sub.3)                                                               8.08 (s 1H, aromatic 6- --H)                                                   7.60-7.10 (m, 6H, C.sub.6  --H.sub.5 and CON --H)                              6.28(s, 1H, aromatic 3- --H)                                                   4.6-4.2 (m, 3H, --N --H.sub.2 and CONH . C --H═)                           3.87 (s, 3H, OC --H.sub.3)                                                     3.56 (S, 2H, PhC --H.sub.2)                                                    3.4-3.1 (m, 2H═CH--N(CH.sub.2 Ph)--C --H.sub.2)                            2.3-1.5(m, 8H--C --H.sub.2)                                         ______________________________________                                    

EXAMPLE 5 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]-8-azabicyclo[3.2.1]octyl)benzamide (5)

Following the procedures outlined in Example 4 above, the crude 3β-amino-8-benzyl-nortropane (D5) was converted to pure 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl]-nortropyl)-benzamide (5) (64%), m.p. 188°-9° C. This was identical to that obtained (n.m.r. and mixed mp.) in Example 4 above.

Nomenclature note: Nortropyl ≡(8-azabicyclo-[3,2,1]-octyl)

EXAMPLE 6 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]-octyl])-benzamide (19) ##STR36##

4-Acetylamino-5-chloro-2-methoxy benzoic acid (4.0 g; 0.016 mole) was dissolved in thionyl chloride (40 ml) at 30°, evaporated in vacuo and azeotroped twice with anhydrous toluene (ca. 100 ml). The resulting 4-acetylamino-5-chloro-2-methoxy benzoyl chloride was redissolved in warm anhydrous toluene (ca. 100 ml) treated with triethylamine (5 ml) and 3β-aminotropane (prepared above). The reaction mixture was stirred at room temperature for 2 hours. The mixture was treated with 2.5 N sodium hydroxide (20 ml), the toluene layer was separated and the aqueous layer extracted with chloroform. The combined extracts were evaporated in vacuo and the resulting solid refluxed with an aqueous ethanol (water 5 ml; ethanol 50 ml) solution of potassium hydroxide (2.5 g) for 11/2 hours. The mixture was cooled, ethanol removed in vacuo and the mixture extracted with warm chloroform (5×100 ml). The combined organic extracts were dried (K₂ CO₃) filtered and evaporated in vacuo. Recrystallization of the resulting solid gave 4-amino-5-chloro-2-methoxy-N-(3'β-[8-methyl-8-azabicyclo[3.2.1]-octyl])-benzamide (1.3 g; 30%) as colourless microcrystals, m.p. 249°-250°.

The following compounds were prepared in an analogous manner:

Compounds on Table B with A suffixed are the 4-acetylamino condensation products, prior to base hydrolysis to give the corresponding compound of the unsuffixed number.

    __________________________________________________________________________      ##STR37##                                                                     Compound                                                                             From               isomer      m.pt                                      No.   Intermediate                                                                          R.sub.6   u *   R.sub.5                                                                            R.sub.3                                                                            °C.                                __________________________________________________________________________           +                                                                         6    D26                                                                                    ##STR38##                                                                               0 α                                                                            Me  NH.sub.2                                                                           172.5                                     11    D10                                                                                    ##STR39##                                                                               1 α                                                                            H   NH.sub.2                                                                           199                                       13    D12                                                                                    ##STR40##                                                                               0 β                                                                             H   NH.sub.2                                                                           213-5                                     14    D13                                                                                    ##STR41##                                                                               0 β                                                                             H   NH.sub.2                                                                           175-8                                     15    D14                                                                                    ##STR42##                                                                               0 β                                                                             H   NH.sub.2                                                                           164-6                                     16    D5                                                                                     ##STR43##                                                                               0 β                                                                             H   NH.sub.2                                                                           212-3                                     17    D6                                                                                     ##STR44##                                                                               0 β                                                                             H   NH.sub.2                                                                           191-5                                     18    D15    CH.sub.2 CH.sub.2 Ph                                                                     0 β                                                                             H   NH.sub.2                                                                           222                                         18A D15    CH.sub.2 CH.sub.2 Ph                                                                     0 β                                                                             H   NHAc                                                                               224                                       20    D26    Me        0 α                                                                            H   NH.sub.2                                                                           219-220                                     20A D26    Me        0 α                                                                            H   NHAc                                                                               178-9                                     21    D25    Me        1  α*                                                                          H   NH.sub.2                                                                           218-220                                   22    D16    Me        1  β*                                                                           H   NH.sub.2                                                                           208-9                                       23++                                                                               D17    Et        0 β                                                                             H   NH.sub.2                                                                           187                                         23A D17    Et        0 β                                                                             H   NHAc                                                                               157                                       24    D18    Pr.sup.n  0 β                                                                             H   NH.sub.2                                                                           205                                         24A D18    Pr.sup.n  0 β                                                                             H   NHAc                                                                               140                                       25    D19    Pr.sup.i  0 β                                                                             H   NH.sub.2                                                                           183                                       26    D20    Bu.sup.n  0 β                                                                             H   NH.sub.2                                                                           224-6                                     27    D29    Bu.sup.n  0 α                                                                            H   NH.sub. 2                                                                          205-6                                     28    D21    CH.sub.2 Pr.sup.i                                                                        0 β                                                                             H   NH.sub.2                                                                           206-7                                     29    D22    CH(Me)Et  0 β                                                                             H   NH.sub.2                                                                           195-7                                     30    D23                                                                                    ##STR45##                                                                               0 β                                                                             H   NH.sub.2                                                                           253-4                                     31    D24                                                                                    ##STR46##                                                                               0 β                                                                             H   NH.sub.2                                                                           278                                         31A D24                                                                                    ##STR47##                                                                               0 β                                                                             H   NHAc                                                                               207                                       32    D30    CH.sub.2 CHCH.sub.2                                                                      0 β                                                                             H   NH.sub.2                                                                           173-5                                     __________________________________________________________________________      + Prepared as described in Description 4A                                        Prepared as described in Description 3D                                      ++as the crystalline hemihydrate                                               *provisional assignment                                                  

The following compounds may be prepared analogously: ##STR48##

EXAMPLE 7 4-Amino-5-chloro-2-methoxy-N-methyl-N-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]benzamide, (6), and 4-amino-5-chloro-2-methoxy-N-methyl-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl)benzamide, (7) ##STR49##

Treatment of (D 27) prepared as in Description 4B with 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride and hydrolysis as outlined in Example 6 gave 4-amino-5-chloro-2-methoxy-N-methyl-N-(3β-[8-benzyl-8-azabicyclo-[3.2.1])-benzamide (7), m.p. 180° and 4-amino-5-chloro-2-methoxy-N-methyl-N-(3α-[8-benzyl-8-azabicyclo-[3,2,1]-octyl])-benzamide (6), m.p. 173° separated by chromatographic elution with ether/ethyl acetate from silica.

The latter compound was identical with Compound 6 prepared in Example 6 from the α-amino intermediate (D 26), in turn prepared as in Description 4A.

EXAMPLE 8 5-Sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl]-8'-azabicyclo-[3.2.1]-octyl)-benzamide (8) ##STR50##

5-sulphamoyl-2-methoxybenzoic acid (2.0 g., 0.009 mole) was dissolved in anhydrous dimethylformamide (20 ml), treated with triethylamine (0.83 g, 0.009 mole) and cooled to 0°. Ethylchloroformate (0.95 g., 0.009 mole) was added dropwise and the solution left to stir for 15 minutes. 3β-Amino-8-benzyl-8-azabicyclo-[3.2.1.]-octane (D4) (1.9 g., 0.09 mole) [prepared as outlined in Description 3B] was added in one portion at 0°. The mixture was left to stand overnight, evaporated to dryness, treated with water (5 ml) and dilute ammonia (10 ml) to give 5-sulphamoyl-2-methoxy-N-(3'β-[8-benzyl-8-azabicyclo-[3,2,1]-octyl)-benzamide (38%), m.p. 213°-214°.

EXAMPLE 9 2-Methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide (9) ##STR51##

3β-Amino-8-benzylnortropane (D4) (1.01 g., 4.67 mmoles) in dry toluene (15 ml) was added to a solution of 2-methoxybenzoyl chloride (made by the reaction of thionyl chloride with 0.78 g. anisic acid) in dry toluene containing 2 ml of triethylamine. The mixture was stirred at ambient temperature for 12 hours then poured into water which was made alkaline by the addition of solid sodium carbonate. The mixture was extracted with ethyl acetate (3×200 ml). Subsequent drying (Na₂ SO₄) and removal of solvent followed by chromatography on silica gel gave the pure 2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo-[3.2.1]-octyl)-benzamide (1.03 g., 63%) as an oil, m.pt. (HCl salt) 269° C.

EXAMPLE 10 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl)-benzamide methobromide (10) ##STR52##

Bromomethane (5 ml) was added to 4-amino-5-chloro-2-methoxy-N-[3β'-(8'-benzyl-nortropyl)]-benzamide (6) (1.0 g) in anhydrous acetone (50 ml) and the solution allowed to stand at ambient temperature for 3 days. The solid produced was filtered off and recrystallised from methanol/ethyl acetate to give 4-amino-5-chloro-2-methoxy-N-[3β-(8-benzyl-8-azabicyclo[3.2.1]octyl)-benzamide methobromide (0.63 g; 53% m.p. 222°-5°.

EXAMPLE 11 4-Amino-5-chloro-2-methoxy-N-(3'α-[9'-azabicyclo[3.3.1]nonyl)benzamide (11) and 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-benzyl-9'-azabicyclo-[3.3.1]-nonyl])-benzamide (12) ##STR53##

Reaction of 3αβ-amino-9-benzyl-9-azabicyclo[3.3.1]nonane (D9) prepared as in Description 3B with 4-acetylamino-5-chloro-2-methoxy-benzoyl chloride and hydrolysis as outlined in Example 6 gave 80-90% 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-benzyl-9'-azabicyclo-[3.3.1]-nonyl)-benzamide (12) m.p. 224°-225° and 10-20% 4-amino-5-chloro-2-methoxy-N-(3'α-[9'-benzyl-9'-azabicyclo-[3,3,1]-nonyl)-benzamide (11) m.p. 199°, separated by chromatographic elution from silica with ethyl acetate/petrol-ether 60°-80°.

The latter compound, m.p. 199°, is indentical to Compound 11 prepared in Example 6 from the α-amine (D10), in turn prepared as in Description 3D.

EXAMPLE 12 4-Amino-5-chloro-2-methoxy-N(2'-(±)-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide (37)

This compound was prepared analogously to Example 6 from (D 31).

M.pt. 218°-9° C.

The product is a racemate of a single diastereomer, believed to be the (±)-α-isomer.

EXAMPLE 13 5-chloro-2-methoxy-4-methylamino-N-[3β-(8'-benzyl-9'-azabicyclo-(3.2.1)octyl)]benzamide (33) ##STR54## Pentachlorophenyl 5-chloro-2-methyoxy-4-methylamino)benzamide (D32) (1 g.) was treated with 3β-amino-8-benzyl-8-azabicyclo(3.2.1)octane (0.47 g) in dimethyl formamide (15 ml) at 80° for 24 hours. The mixture was evaporated to a thin film, then poured into stirred water. The white crystals were filtered, dried in vacuo and chromatographed on 5% deactivated alumina (Brockman 1) using ethyl acetate as eluant. The recovered material was recrystallised from ethyl acetate and light petroleum 60/80 to give 5-chloro-2-methoxy-4-methylamino-N[3β-(8'-benzyl-8'-azabicyclo(3.2.1)octyl)]benzamide, m.pt 156°-157° C. PHARAMACOLOGICAL DATA

The following Section illustrates the pharmacological activity of compounds of the formula (I).

I. Dopamine Receptor Blocking Activity in the Central Nervous System (a) Inhibition of apomorphine induced stereotype behaviour in the rat

(method of Ernst (1967), Psychopharmacologia (Berl.) 10 316-323). Table I shows the dose for complete inhibition.

Compounds marked IA () are inactive at the dose in the brackets, mg/Kg s.c. (b) Inhibition of apomorphine induced climbing in the mouse The test is based on that described by Protais, P., Constantin, J. and Schwartz J.C. (1976), Psychopharmacology, 50, 1-6.

Apomorphine 1 mg/kg s.c. induces mice to climb the wall of a wire cage (inverted food hopper--11×7.5×18 cm high). Mice acclimatised in their home cages in groups of 5 are placed under the hoppers immediately after the injection of apomorphine 1 mg/kg s.c. At 10,20 and 30 minutes after injection climbing behaviour is scored. The mice are observed for 30 seconds and scored according to the position they spend the majority of time in, score 0--four paws on floor of cage; score 1--fore paws only on walls; score 2--all paws on wall of cage. The scores at all 3 times and for each mouse are summed and mice drug treated orally compared to mice receiving apomorphine only. A saline only treated group is also included and any score, generally <5% of maximum taken into account.

Table I shows the dose for complete inhibition, or the ED₅₀. Compounds marked IA were inactive at 10 mg/Kg p.o.

(c) In vitro displacement of radiolabelled spiroperidol from dopamine receptor membranes

[3H]-spiroperidol has been shown to bind with high affinity to dopamine receptors in the brain (Greese, I., Schneider, R. and Snyder, S. H., European J. Pharmac., 46 [1977], 377-381; Leysen, J. E., Gommeren, W. and Laduron, P. H. Biochem. Pharmac., 27, [1978]. 307-316). Therefore a compound which displaces this ligand from dopamine receptor membranes may have neuroleptic properties.

Male Hooded Lister rats (200-300 g) are decapitated and the caudate nucleus is quickly dissected out. This is homogenised in ice cold Tris buffer (pH 7.7 at 25° C.) at a concentration of 10 mg/ml wet weight of tissue. The test compound (at 10⁻⁵ M) or spiroperidol (standard curve from 10⁻⁵ to 10⁻⁹ M) is added to the assay tubes followed by 0.5 nM [³ H]-spiroperidol. This is mixed with 500 μl of the membrane preparation and the assay tubes are incubated for 15 minutes at 37° C. After this period 4 ml ice cold Tris buffer is added to each tube and the solutions are filtered through pre-soaked glass fibre filters. The filter is washed twice with 4 ml of the buffer and then transferred to a scintillation vial for counting. Single concentration results are given as a percentage of [³ H]-spiroperiodol displaced. Table I shows the percentage displacement at 10⁻⁵ M concentration of the compound, or the concentration for 50% displacement (ED₅₀). Compounds displacing less than 50% at 10⁻⁵ M are not shown in Table I.

II. Anti-emetic activity in the dog

Compounds were administered subcutaneously 30 minutes prior to administration of a standard dose of apomorphine HCl (0.1 mg/kg subcutaneously) and the vomiting response compared to that obtained when the same animals were dosed with apomorphine HCl and vehicle only. The dose that totally inhibited the vomiting response was determined in the same instances, the ED₅₀ in others.

III. Gastric Activity (a) Increase in intragastric pressure in the rat

Intragastric pressure changes were recorded from previously starved conscious but restrained rats using a saline filled catheter inserted into the lumen of the stomach via a permanent gastric fistula. The catheter was connected to a physiological pressure transducer and pressure changes recorded on a hot wire pen recorder. In each animal a pre-dose period of 40 minutes was allowed to obtain a measure of spontaneous activity. An index of activity was obtained by measuring the average height of pressure waves during 10 minute periods. Values for 4 such periods were obtained during assessment of spontaneous activity and for the 40 minute period after the subcutaneous administration of the compounds. Students `t` test was applied to the difference in average values obtained for spontaneous and post-compound activity.

Table II shows the miniumum dose for activity. Compounds marked IA () are inactive at the dose in the brackets, mg/Kg s.c.

(b) Increase in gastric emptying: reversal of apomorphine induced delay in gastric emptying in the rat

Rats equipped with chromic gastric fistulae were used and it was through this that 5 ml of a test meal (5 ml phosphate buffer at pH 9) was administered and recovered. The % recovery of the standard meal after remaining in the stomach for 10 minutes was taken as an index of gastric emptying. Delay in gastric emptying was induced by the administration of apomorphine HCl (5 mg/kg subcutaneously) which was given 15 minutes prior to the subcutaneous administration of the compound. The % recoveries of the test meal were determined at 15-25 and 45-55 minutes post-dosing with the compound and compared with vehicle only dosed animals set up simultaneously. Six animals were used for each group.

Table II shows the % increase in gastric emptying for 10 mg/kg s.c. of the compound.

In addition the % recoveries for compound 2 are shown in the Table immediately below.

                  TABLE                                                            ______________________________________                                                        % Recovery of test meal.                                                       Mean values ± S.E. of mean                                                  Time interval post dosing                                                      with vehicle or compounds                                       Treatment        15-25 mins. 45-55 mins.                                       ______________________________________                                         (1) Apomorphine + vehicle                                                                       72.4 ± 5.1                                                                              60.7 ± 7.3                                     (2) Apomorphine + vehicle                                                                       37.4 ± 6.7**                                                                            18.3 ± 1.1***                                  (2) 10 mg/kg s.c.                                                              ______________________________________                                          Significantly different from apormorphine + vehicle group set up               simultaneously **p<0.01 ***p<0.001.                                      

At 10 mg/kg subcut. the % recovery of test meal was significantly decreased at both the 15-25 and 45-55 minute time intervals and therefore gastric emptying was increased.

Compound 5 significantly increases gastric emptying at a dose of 0.05 mg/kg s.c.

                  TABLE I                                                          ______________________________________                                                       I(b)                                                             I(a)          Anti-Climbing                                                    Dose          Activity     I(c)                                                Inhibiting    Dose mg/kg   Spiroperidol                                        Stereotype    p.o.         Displacement                                                Behaviour Complete       %      ED.sub.50                              Compound                                                                               mg/kg s.c.                                                                               Inhibition                                                                              ED.sub.50                                                                            at 10.sup.-5 M                                                                        M×10.sup.-7                      ______________________________________                                         2       10                                                                     3       50                                                                     5       0.05               0.03                                                6       IA(50)    IA                                                           8                 IA                                                           9                 10                                                           10                IA(2)                                                        11      IA(50)    IA                                                           12      0.5        2             53                                            13                         0.12  54                                            14                10                                                           15                10                                                           16                 2                                                           18      IA(50)    IA                    6                                      19      IA(25)    IA             64                                            21      IA(50)    10                                                           22      IA(25)    IA                                                           23      IA(25)    IA                                                           24      IA(25)    IA                                                           25      IA(25)    IA                                                           26                         2.9          4                                      27      IA(10)    IA             66                                            28                                                                             30      *          5                    2 × 10.sup.-1                    31                IA                                                           ______________________________________                                            lower levels not tested;                                                       slight at 1;                                                                 * slight at 0.05                                                         

                  TABLE II                                                         ______________________________________                                                            III (a)                                                     II                 Increase in                                                                               III (b)                                          Anti-Emetic Activity                                                                              Intragastric                                                                              Increase                                         Dose, mg/kg s.c.   Pressure   in Gastric                                               Complete           Dose, mg/kg                                                                             Emptying                                   Compound                                                                               Inhibition                                                                               ED.sub.50                                                                               s.c.     %                                          ______________________________________                                         2       0.0025                                                                 3       0.05                                                                   5       0.001                                                                  6                          10       IA(50)                                     8       0.1                IA(5)                                               9       0.1                                                                    10      IA                 0.25                                                11      IA                 1                                                   12      0.1                IA(1)                                               13      0.1                                                                    14      0.1                                                                    15      0.1                                                                    16                                                                             18      0.25               IA(5)                                               19      1.6                1-10     25                                         21                         5                                                   22                         1        IA(25)                                     23      1.6                1-10     25                                         24      0.4                5-10     IA(25)                                     25                0.8      5        IA                                         26      0.4                         1                                          27      1                  IA(10)   IA(10)                                     28      0.2                5                                                   30      *                  IA(1)    0.05                                       31      0.25                                                                   32      0.2                                                                    ______________________________________                                          * slight at 5 × 10.sup.-4 ;                                               see Pharmacological Data, III(b)                                        

For the sake of completeness it should be mentioned that single compound tests have shown Compound 5 to have anti-obesity activity and Compound 20 to have antiarrhythmic activity.

Toxicity

In the tests reported above no toxic effects were observed. 

We claim:
 1. A compound of the formula (I) and pharmaceutically acceptable salts thereof: ##STR55## wherein: R₁ is a C₁₋₆ alkoxy group;R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇ acyl, C₂₋₇ acylamino, or amino or aminocarbonyl optionally substituted by one or two C₁₋₆ alkyl groups, or nitro; R₅ is hydrogen or C₁₋₆ alkyl; R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 0 to 2 and R₇ is a C₃₋₈ cycloalkyl group, or a group --(CH₂)_(t) R₈ where t is 1 or 2 and R₈ is C₂₋₅ alkenyl or a phenyl group optionally substituted by one or two substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen; and n, p and q are independently 0 to
 2. 2. A compound according to claim 1, whereinR₁ is a C₁₋₆ alkoxy group; R₂ and R₃ are the same or different and are hydrogen, halogen, CF₃, C₂₋₇ acyl, amino, C₂₋₇ acyl amino or aminocarbonyl optionally subsituted by one or two C₁₋₆ alkyl groups; or nitro groups. R₅ is hydrogen or C₁₋₆ alkyl; R₆ is C₁₋₇ alkyl or a group --(CH₂)_(s) R₇ where s is 1 or 2 and R₇ is a C₃₋₈ cycloalkyl group, or a phenyl group optionally substituted by one or two substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen; and n, p and q are independently 0 to
 2. 3. A compound according to claim 2 of the formula (IV): ##STR56## wherein R₆ is as defined in claim
 2. 4. A compound according to claim 3 of the formula (VII): ##STR57## wherein R¹ ₆ is C₁₋₄ alkyl.
 5. A compound according to claim 4, wherein the moiety of the formula (III) ##STR58## is in the β-orientation to the nortropane ring.
 6. 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]octyl)benzamide or a pharmaceutically acceptable salt thereof.
 7. 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]octyl)benzamide or a pharmaceutically acceptable salt thereof.
 8. 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-iso-butyl-8'-azabicyclo[3.2.1]octyl)benzamide or a pharmaceutically acceptable salt thereof.
 9. A compound according to claim 3 of the formula (VIII): ##STR59## wherein R² ₆ is C₅₋₇ alkyl; a group --(CH₂)_(t) R¹ ₈ wherein t is 1 or 2 and R¹ ₈ is optionally substituted phenyl as defined in claim 1; or cyclohexylmethyl.
 10. A compound according to claim 9, wherein R² ₆ is a group --(CH₂)_(t) R¹ ₈ wherein t is 1 or 2 and R¹ ₈ is a phenyl group optionally substituted by one or two substituents selected from C₁₋₆ alkyl, C₁₋₄ alkoxy, trifluoromethyl and halogen.
 11. A compound according to claim 9, wherein the the moiety of the formula (III): ##STR60## is in the β-orientation to the nortropane ring.
 12. A compound according to claim 11, wherein R² ₆ is benzyl.
 13. 4-Amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl)benzamide or a pharmaceutically acceptable salt thereof.
 14. A pharmaceutical composition having dopamine antagonist activity comprising a dopamine antagonist effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
 15. A method of treatment of humans suffering from emesis, impaired gastro-intestinal motility or disorders of the central nervous system, which method comprises the administration to the sufferer of an effective amount of a compound as claimed in claim 1 sufficient to overcome the emesis, impaired gastro-intestinal motility or disorder of the central nervous system.
 16. A compound according to claim 1 wherein R₁ is methoxy, ethoxy or n-or iso-propoxy.
 17. A compound according to claim 16 wherein R₁ is methoxy.
 18. A compound according to claim 1 wherein R₂ and R₃ are each independently hydrogen, chlorine, bromine, acetyl, CF₃, propionyl, n- and iso-butyryl, acetylamino, propionylamino, n- and iso-butyrylamino, amino or aminocarbonyl, substituted by one or two methyl, ethyl, n- or iso-propyl, or n-, sec- or tert-butyl groups.
 19. A compound according to claim 18 wherein R₂ is in the 4-position relative to the carbonyl side-chain.
 20. A compound according to claim 18 wherein R₂ is 4-amino or 4-acylated amino.
 21. A compound according to claim 18 wherein R₃ is in the 5-position relative to the carbonyl side-chain.
 22. A compound according to claim 21 wherein R₃ is 5-halo.
 23. A compound according to claim 22 wherein R₃ is 5-chloro.
 24. A compound according to claim 18 wherein the amide and side-chain nitrogen atoms are separated by a minimum of 2 or 3 carbon atoms.
 25. A compound according to claim 24 wherein the amide and side-chain nitrogen atoms are separated by a minimum of 3 carbon atoms.
 26. A compound according to claim 1 wherein R₅ is hydrogen, methyl, ethyl, n- or iso-propyl or n-, sec- or tert-butyl.
 27. A compound according to claim 26 wherein R₅ is hydrogen.
 28. A compound according to claim 1 wherein R₆ is methyl, ethyl, n- or iso-propyl, or n-, sec-, iso, or tert-butyl, n-pentyl, n-hexyl or n-heptyl.
 29. A compound according to claim 4 wherein the bond between the benzamide moiety and the cyclic side-chain is equatorial.
 30. A compound according to claim 1 wherein the pharmaceutically acceptable salts are acid addition salts or quaternary ammonium salts.
 31. A compound according to claim 1 selected from:4-acetamido-5-chloro-2-methoxy-N-(3α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-methyl-(3'α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-methyl-(3'-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 5-sulphamoyl-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide, 2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzyl methobromide 4-amino-5-chloro-2-methoxy-N-(3α'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3β'-[9'-benzyl-9'-azabicyclo[3.3.1]nonyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-methylbenzyl]-8'-azabicyclo-[3.2.1]-octyl]-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-methoxybenzyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[4"-ethoxybenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'[4"-chlorobenzyl]-8'-azabicyclo-[3.2.1]octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-[3",4"-dichlorobenzyl]-8'-azabicyclo-(3.2.1]octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide, 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-β-phenethyl]-8'-azabicyclo-[3.2.1]-octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-methyl-8'-azabicyclo[3.2.1]-octyl)-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'α-[8'-methyl-8'-azabicyclo[3.2.1]-octyl)-benzamide 4-acetamido-5-chloro-2-methoxy-N-(3'α-[8'methyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'α-[9'-methyl-9'-azabicyclo[3.3.1]nonyl benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[9'-methyl-9'-azabicyclo[3.3.1]-nonyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-ethyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-ethyl-8'-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide, 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-n-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-iso-propyl-8'-azabicyclo[3.2.1]-octyl])benzamide 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'α-[8'-n-butyl-8'-azabicyclo[3.2.1]-octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-secbutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-isobutyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexylmethyl-8'-azabicyclo-[3.2.1]-octyl])-benzamide 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl])benzamide, 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-cyclohexyl-8-azabicyclo[3.2.1]octyl]benzamide, 4-amino-5-chloro-2-methoxy-N-(3'β-[8'-allyl-8-azabicyclo[3.2.1]octyl])benzamide, 5-chloro-2-methoxy-4-methylamino-N-(3β-[8'-benzyl-8-azabicyclo[3.2.1]octyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[8'-methyl-''-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-emthoxy-N-(2'-(-)-β-[8'-methyl-8'-azabicyclo[3.2.1]octyl]methyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(-)-α-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(+)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(2'-(-)-β-[7'-benzyl-7'-azabicyclo[2.2.1]heptyl)benzamide, 4-amino-5-chloro-2-methoxy-N-(4'-(+)-α[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(4'-(-)-α-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide, 4-amino-5-chloro-2-methoxy-N-(4'-(+)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide, and 4-amino-5-chloro-2-methoxy-N-(4'-(-)-β-[9'-benzyl-9'-azabicyclo[4.2.1]nonyl])benzamide
 32. A pharmaceutical composition according to claim 14 wherein the compound has a balance between peripheral and central action useful in the treatment of disorders related to impaired gastrointestinal motility including retarded gastric emptying, dyspepsia, flatulence, oesophagal reflux, peptic ulcer and emesis and having anti-psychotic activity.
 33. A composition according to claim 32 wherein the motility enhancing activity comprises those compounds wherein R₆ contains 1-4 carbon atoms.
 34. A composition according to claim 33 wherein R₆ is C₁₋₄ alkyl.
 35. A pharmaceutical composition according to claim 32 wherein those compounds in which R₆ contains at least 5 carbon atoms are characterized by central-nervous-system activity and anti-emetic activity.
 36. A pharmaceutical composition according to claim 35 wherein R₆ is benzyl.
 37. A pharmaceutical composition according to claim 14 formulated for oral or parenteral administration.
 38. A pharmaceutical composition according to claim 37 wherein the oral or parenteral administrable form comprises compressed tablets, capsules, oral liquids, powders, granules, lozenges, reconstitutable powders and injectable and infusable solutions or suspensions and syrups and suppositories.
 39. A pharmaceutical composition according to claim 38 wherein the composition is formulated in unit-dosage, orally-administrable form of which each unit dosage contains an effective amount of a compound of formula (I).
 40. A method according to claim 15 wherein the compound is present in a therapeutically-effective amount of a compound of formula (VI).
 41. The compound of claim 31 which is 4-acetamido-5-chloro-2-methoxy-N-(3'β-[8'-benzyl-8'-azabicyclo[3.2.1]octyl])benzamide having a melting point of 185° C. 